Montelukast

Montelukast belongs to the pharmacological class leukotriene receptor antagonist. Montelukast binds to the CysLT₁ , as it has greater affinity to this receptor.

Montelukast has been approved for relieving symptoms and also for the treatment and maintenance of episodes of asthma, allergic rhinitis, exercise-induced bronchospasm, urticaria.

Montelukast is completely and rapidly absorbed with an oral bioavailability of 64%. Montelukast achieved a mean volume of distribution of 8-11 litres. The Montelukast is found to be metabolized by the cytochrome P450 3A4, 2C8, and 2C9 isoenzymes. The plasma clearance documented for montelukast suggests that 45ml/min clearance has been observed in adults.

The common side effects associated with Montelukast are headache, fever, diarrhea, stomach ache , high temperatures, tiredness etc.

Montelukast is available in the form of chewable and film-coated tablets and granules Montelukast is available in U.S., Canada,E.U.,India

Montelukast belongs to the pharmacological class leukotriene receptor antagonist. Montelukast binds to the CysLT₁ , as it has greater affinity to this receptor.

Hence Montelukast inhibits the physiologic action of the LD₄ in CysLT₁ receptor without rendering any agonistic activity. This, in turn, reduces inflammations and relives from the symptoms associated with conditions such as allergic rhinitis, urticaria, exercise induces bronchospasm.

Montelukast has onset of action is within 2hrs and duration of action lasts about 3-4 hrs

The mean Montelukast for 4 mg granules , Cmax was found to be 178.04 ± 41.58. ng/mL and Tmax to be 2.75.

Montelukast is available in chewable and film-coated tablets and granules and should be swallowed whole with water

Montelukast can be used in the treatment of:

• Allergic rhinitis
• Exercise induces bronchospasm
• Asthma maintenance therapy
• Hypersensitivity reactions, rapid chemotherapy/biologics desensitization.
• Infusion related reactions ,daratumumab-based regimes premedication.
• Urticaria

Montelukast can help to relieve symptoms and also for the treatment and maintenance of episodes asthma, allergic rhinitis, exercise-induced bronchospasm, urticaria.

Montelukast is approved for use in the following clinical indications:

• Allergic rhinitis
• Exercise induces bronchospasm
• Asthma maintenance therapy
• Hypersensitivity reactions, rapid chemotherapy/biologics desensitization (off-label)
• Infusion related reactions ,daratumumab-based regimes premedication(off-label)
• Urticaria

Montelukast can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgment of the treating physician.

Adults dosage:

Allergic rhinitis (seasonal /perennial): 10mg once a day

Aspirin exacerbated respiratory disease including aspirin challenge or desensitization (off label use): 10mg once daily in the evening

Asthma maintenance therapy. 10mg once a day in the evening

Bronchoconstriction: 10 mg before to 2 hrs of exercise and limit the dose to once daily every 24 hrs.

Hypersensitivity reactions, rapid chemotherapy/biologics desensitization (premedication) (off-label use): 10 mg once a day for two days before the sensitization procedure and 10mg 1hr before the procedure

Infusion-related reactions, daratumumab-based regimens (premedication) (off-label use): 10 mg is administered 30 to 60 minutes prior to the first infusion. 10mg is administered on day 1 and on day 2 it is administered as a part of the premedication regimen.

Pediatric

Allergic Rhinitis:

Perennial

Infants aged more than 6 months and less than 6 years of age: oral 4mg once daily

Children aged more than 6 years and adolescents aged less than 15 years: 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Seasonal

Children between aged 2 to 5 years: 4 mg oral dose once daily

Children more than aged 6 years and adolescents less than 15 years of age: 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Asthma maintenance therapy

Children between 12 months to 5 years of age: 4 mg oral dose once daily in the evening

Children aged more than 6 years and adolescents aged less than 15 years : 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Exercise-induced bronchospasm:

It is advised that additional doses should not be administered within 24 hours of the initial dose. Daily dose for administration to prevent the exercise-induced bronchospasm has not been evaluated. Patients who have receive montelukast for another indication or treatment should not take an additional dose to prevent exercise-induced bronchoconstriction.

Children aged more than 6 years and adolescents less than 15 years of age: 5mg once daily two hours before exercise

Adolescents more than 15 years of age: oral 10mg once daily two hours before exercise

Urticaria

Adolescents more than 15 years of age: oral 10mg once daily.

Chewable tablet, Film-coated tablet, Oral granules

• Dosage Adjustments in Pediatric Patients: 

Due to the risk associated with leading to neuropsychiatric events , Montelukast should be used only if the benefits outweigh the risk associated.

Allergic Rhinitis:

Perennial

Infants agents more than 6 months and less than 6 years of age: oral 4mg once daily

Children aged more than 6 years and adolescents aged less than 15 years : 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Seasonal

Children between aged 2 to 5 years : 4 mg oral dose once daily

Children aged more than 6 years and adolescents aged less than 15 years : 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Asthma maintenance therapy

Children between 12 months to 5 years of age: 4 mg oral dose once daily in the evening

Children aged more than 6 years and adolescents aged less than 15 years : 5mg once daily

Adolescents more than 15 years of age: oral 10mg once daily

Exercise-induced bronchospasm:

It is advised that additional doses of Montelukast should not be administered within 24 hours. The daily dose for administration to prevent the exercise-induced bronchospasm has not been evaluated. Patients who receive montelukast for another indication or treatment measure should not take an additional dose of the same medication to prevent exercise-induced bronchoconstriction.

Children more than aged 6 years of age and adolescents aged less than 15 years : 5mg once daily two hours before exercise

Adolescents more than 15 years of age: oral 10mg once daily two hours before exercise

Urticaria

Adolescents more than 15 years of age: oral 10mg once daily.

Smoking cessation and maintaining health is a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient’s especially with an underlying liver disorder or liver dysfunction

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions is needed to be individualized as per the patient's requirements.

Montelukast maybe contraindicated during the co-administration with the following drugs:

• Hypersensitivity to the ingredients of the medication

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Acute Asthma

Montelukast is not found to be indicated for use in the reversal of bronchospasm in episodes of acute asthma attacks, including a condition called as status asthmaticus. Patients should be advised to have an appropriate rescue medication available. Therapy with Montelukast can be continued during episodes of acute exacerbations of asthma. Patients suffer from exacerbations of asthma after exercise should use a rescue such as short-acting inhaled ß-agonist.

Concomitant Corticosteroid Use

While the dose of inhaled corticosteroid can be reduced gradually under the medical supervision, Montelukast should not be immediately substituted for inhaled or oral corticosteroids.

Aspirin Sensitivity

Patients who have known aspirin sensitivity shall continue avoiding aspirin or non-steroidal anti-inflammatory agents while using Montelukast.Although Montelukast is found to be effective in improving the airway function in asthmatics with pro aspirin sensitivity.

Neuropsychiatric Events

Neuropsychiatric events have been reported in adults, adolescent, and pediatric patients who use Montelukast. Post-marketing reports with Montelukast use include irritability, restlessness, somnambulism, suicidal thinking ,disorientation, dream abnormalities, hallucinations, insomnia and behavior (including suicide), agitation, aggressive behavior or hostility, anxiousness, depression, and tremor. The clinical details of some post-marketing reports which involve Montelukast appears to be consistent with a drug-induced effect. Patients and prescribers should be alert for the neuropsychiatric events. Patients should be advised to notify their physician'sif these changes occur. Prescribers must carefully evaluate the benefits and risks associated with continuing treatment with Montelukast if such events occur

Eosinophilic Conditions

Patients suffering from asthma on therapy with Montelukast might present with systemic eosinophilia, which sometimes presented with clinical features of vasculitis consistent with a condition called Churg-Strauss syndrome, which is a condition that is often treated with a systemic corticosteroid therapy. These events have been usually associated with the reduction of oral corticosteroid therapy. Physicians should be alert to cardiac complications,eosinophilia, vasculitic rash, worsening pulmonary symptoms, and/or neuropathy presenting in their patients.

Phenylketonuria

Patients suffering from Phenylketonuria should be informed that the 5 mg and 4 mg chewable tablets consists of phenylalanine which is a component of aspartame, in the concentrations of 0.674 and 0.842 mg per 5 mg and 4 mg chewable tablet, respectively.

Avoid alcohol usage while on Montelukast medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision etc.

Studies in rats have shown that montelukast is found to be excreted in milk. It is not known whether montelukast is excreted in human milk, hence caution should be exercised when Montelukast is prescribed to a nursing mother.

Teratogenic Effects

Pregnancy Category B: There are no adequate as well as well-controlled studies in pregnant women. The animal reproduction studies are not always predictive of human response, hence Montelukast can be used during pregnancy only if the benefits outweighs the risk associated.

Teratogenic Effect: No teratogenicity had been observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs . During worldwide marketing experience, some congenital limb defects have been rarely reported with Montelukast during pregnancy. A causal relationship between these events and offspring of women being treated Montelukast has not been established.

No sufficient scientific evidence traceable regarding the use and safety of Montelukast in concurrent use with any particular food. Montelukast can be taken without regard to the food or meals.

The adverse reactions related to Montelukast can be categorized as:

Common

• Pain or tenderness around the eyes and cheekbones
• Pain, redness, or swelling in the ear
• Stomach pain
• Stuffy or runny nose
• Tender, swollen glands in neck
• Trouble in swallowing
• Unusual tiredness or weakness
• Voice changes
• Body aches or pain
• Cough
• Difficulty in breathing
• Dryness or soreness of the throat
• Fever
• Headache
• Loss of voice

Less common

• Joint pain
• Sweating
• Bloody nose
• General feeling of discomfort or illness

Rare

• Pus in the urine

The clinically relevant drug interactions of Montelukast is briefly summarized here:

No dose adjustment is necessary when Montelukast is co-administered with prednisone, prednisolone, theophylline,oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative-hypnotics, non-steroidal anti-inflammatory agents, benzodiazepine, Cytochrome P450 (CYP) enzyme inducers and decongestants.

Gemfibrozil: Might increase the serum concentration of Montelukast. Monitoring therapy is advised

Loxapine: Agents used to treat Airway Disease might enhance the toxic/adverse effect of Loxapine. The agents used to treat airway disease is likely used as a marker in patients who are more likely at a greater risk of experiencing significant bronchospasm from use of loxapine inhalation.

Management: There is specification to the Adasuve brand of loxapine, which is used as an inhaled formulation.Hence, it is advised to avoid combination.

Lumacaftor and Ivacaftor: Might decrease the serum concentration of Montelukast. Risk C: Hence it is advised to monitor therapy.

The common side effects of Montelukast include the following:

• High temperatures
• Headaches
• Mild rash
• Stomach ache
• Diarrhea
• Tiredness
• Fever
• Sore throat hoarseness

Teratogenic Effects

Pregnancy Category B: There are no adequate as well as well-controlled studies in pregnant women. The animal reproduction studies are not always predictive of human response, hence Montelukast should be used during pregnancy only if the benefits outweighs the risk associated.

Teratogenic Effect: No teratogenicity had been observed in rats and rabbits at doses approximately 100 and 110 times, respectively. During worldwide marketing experience, some congenital limb defects have been rarely reported with Montelukast during pregnancy. A causal relationship between these events and offspring of women being treated Montelukast has not been established.

Nursing Mothers

Animal studies in rats have shown that montelukast is found to be excreted in milk. It is not known whether montelukast is excreted in human milk, hence caution should be exercised when Montelukast is prescribed to a nursing mother.

Pediatric Use

The safety and efficacy of Montelukast has been established in some adequate and well-controlled studies in pediatric patients suffering from asthma aged 6 to 14 years.The efficacy and safetyprofiles in this age group have been found to be similar to those seen in adults.

Geriatric Use

Out of the total number of subjects who participated in clinical studies of montelukast, 3.5% were aged 65 years and over, and 0.4% were aged 75 years and over. No overall differences in safety or effectiveness had been observed between these older subjects and younger subjects, and other reported clinical experience had not identified differences in responses between the older and younger patients. But a greater sensitivity in some elderly individuals cannot be ruled out. The oral bioavailability and pharmacokinetic profile of a single 10-mg oral dosage of montelukast are similar in older and younger adults. Although,the plasma half-life of montelukast is found to be slightly longer in the elderly patients. Hence, no dosage adjustment in the elderly is required.

Physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Montelukast.

No mortality has occurred following single oral doses of montelukast, which is up to 5000 mg/kg in rats and mice. The specific information is found to be available on the treatment of overdosage with Montelukast medication. In patients suffering from chronic asthma , during clinical studies, montelukast was administered at doses up to 200 mg/day to adult patients for about 22 weeks. In short-term clinical studies, up to 900 mg/day to the patients for approximately a 7 days without clinically important adverse experiences. In the event of overdose, it is reasonable to employ some usual supportive measures such as removal of unabsorbed material from the gastrointestinal tract, employing clinical monitoring, and instituting supportive therapy, if required. There were no adverse experiences observed and reported in the majority of overdosage reports in the post-marketing experience. The frequently occurring adverse experiences were found to be consistent with the safety profile of Montelukast which included thirst, headache, vomiting, abdominal pain, somnolence, and psychomotor hyperactivity. It is not known whether the drug montelukast can be removed by peritoneal dialysis or hemodialysis

Pharmacodynamics

Montelukast is said to cause inhibition of airway cysteinyl leukotriene receptors as it has been shown by the ability to inhibit bronchoconstriction due to inhaled L TD4 in asthmatics. Lower doses of about 5 mg causes substantial blockage of L TD4-induced bronchoconstriction. In a placebo-controlled, crossover study , Montelukast the inhibited early- and late-phase bronchoconstriction due to the antigen challenge by 75% and 57%, respectively. Montelukast's effect on eosinophils in the peripheral blood has been examined in clinical trials in patients suffering from asthma aged 2 years and older . It was found that the patients who received Montelukast, there was found to be a decrease in the mean peripheral blood eosinophil counts ranging between 9% to 15% as compared to placebo, over the double-blind treatment periods. In patients suffering from seasonal allergic rhinitis aged 15 years or older who received Montelukast , there was found to be a mean increase of 0.2% in peripheral blood eosinophil counts, when compared with a mean increase of about 12.5% in placebo-treated patients, over the double-blinded treatment periods. This reflects a mean difference of around 12.3% in favor of Montelukast.

Pharmacokinetics

• Absorption

Montelukast is said to be rapidly absorbed after being orally administered. After administration of the 10-mg film-coated tablet to adults under fasting conditions, the mean peak montelukast plasma concentration (Cmax) was achieved in 3 to 4 hours (T max). The mean oral bioavailability was found to be 64%. The Cmax and oral bioavailability were not influenced by a standard meal taken in the morning. For the 5-mg chewable tablet, the mean Cmax was achieved in 2 to 2.5 hours after administration to adults who were in the fasted state. The mean oral bioavailability was found to be 73% in the fasted state versus 63% when Montelukast was administered with a standard meal in the morning. For a 4-mg chewable tablet, the mean Cmax was achieved in 2 hours after administration in pediatric patients aged 2 to 5 years in the fasted state. The 4-mg chewable tablet formulation is bioequivalent to the 4-mg oral granule when administered to adults in the fasting condition. A high fat meal in the morning did not affect the Area under the curve of Montelukast oral granules. Although ,the meal decreased Cmax by 35% and prolonged T max from 2.3 :t 1.0 hours to 6.4 :t 2.9 hours. The efficacy and safety of Montelukast in patients with asthma were found to be demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg chewable tablet formulations had been administered in the evening without regard to the time of food ingestion. The safety of Montelukast in patients suffering from asthma was also found to be demonstrated in clinical trials in which the 4mg chewable tablet and 4mg oral granule formulations were administered in the evening without regard to the time of food ingestion.

• Distribution

Montelukast is found to be more than 99% bound to plasma proteins. The steady-state volume of distribution of drug montelukast averages from 8 to 11 liters. Studies in rats with radiolabeled montelukast indicated that there is minimal distribution across the blood-brain barrier. In addition, the concentrations of radiolabeled material i.e.Montelukast at 24 hours postdose were found to be minimal in all other tissues.

• Metabolism

Montelukast is said to be extensively metabolized. In studies with therapeutic doses of Montelukast, plasma concentrations of state in adults and pediatric patients. The in-vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C9 enzymes are involved in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of CYP3A4 e.g., erythromycin, ketoconazole, or 2C9 e.g., fluconazole on montelukast pharmacokinetics have not been metabolites of montelukast are undetectable at steady conducted. Based on further in-vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not cause inhibition enzymes such as CYP3A4, CYP2C9, CYP1A2, CYP2A6, CYP2C19, or CYP2D6. The in-vitro studies had shown that montelukast is found to be a potent inhibitor of CYP2C8 enzyme.

• Elimination

The plasma clearance of montelukast averages to about 45 mL/min in healthy adults. After an oral dose of radiolabeled montelukast, about 86% of the radioactivity was found to be recovered in a 5-day fecal collections and 0.2% was found to be recovered in urine. Coupled with the estimates of montelukast oral bioavailability, indicates that montelukast and its metabolites are found to be excreted via the bile. During several studies, it was found that the mean plasma half-life of montelukast ranged between 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are reported nearly linear for oral doses which is up to 50 mg. During once a day dosing with 10-mg montelukast, there is found to be a little accumulation of the parent drug in plasma (14%).

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13. Sarkar M, Koren G, Kalra S, et al, “Montelukast Use During Pregnancy: A Multicentre, Prospective, Comparative Study of Infant Outcomes,” Eur J Clin Pharmacol 2009, 65(12);1259-64.
14. Seidman MD, Gurgel RK, Lin SY, et al; Guideline Otolaryngology Development Group. AAO-HNSF. Clinical practice guideline: Allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(1)(suppl):S1-S43.
15. Simon RA. Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 12, 2021b.
16. Simon RA, Cutlip D. Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 10, 2021a.
17. Singulair (montelukast) [prescribing information]. Jersey City, NJ: Organon LLC; June 2021.
18. Singulair (montelukast) [product monograph]. Kirkland, Quebec, Canada: Organon Canada Inc; May 2021.
19. White AA, Stevenson DD, Woessner KM, Simon RA. Approach to patients with aspirin hypersensitivity and acute cardiovascular emergencies. Allergy Asthma Proc. 2013;34(2):138-142.